text: Sildenafil, the first PDE5 inhibitor, was discovered through rational drug design programme. The compound was potent and selective over PDE5 but was lacking preferable pharmacological properties.
  Structure-activity relationship (SAR) is demonstrated in figure 5, figure 6 and figure 7. Figure 5 demonstrates the three main groups of sildenafil, R1, R2 and R3. R1 is the pyrazolopyrimidinone ring, R2 the ethoxyphenyl ring and R3 is the methylpiperazine ring. R1 group is responsible for the binding of the drug to its active binding site of PDE5.
  Solubility is one of the pharmacological properties that was increased. A group was substituted for the hydrogen atom as demonstrated in figure 6. The sulfonamide group was chosen to lower lipophilicity and increase solubility as seen in figure 7.
  Solubility was further increased by placing a methyl group at R positions as demonstrated in figure 7. Other phosphodiesterase-5 inhibitors were developed from the structure in figure 7.